The Role of Oligodendrocytes in Cognitive Decline after Alcohol and Aging

PROJECT SUMMARY Cognition declines with age, and severe and prolonged use of alcohol (alcohol use disorder, AUD) could be accelerating and worsening these aging processes. The timing and magnitude of cognitive dysfunction correlates with the emergence of white matter loss in frontal and temporal lobes (frontotemporal intercortical myelinated axons), suggesting that myelin deficits may underlie these cognitive changes. However, the direct functional contribution these brain changes may (or may not) have on reduced cognitive abilities after alcohol in aged individuals is unknown, as are the underlying mechanisms. Thus, more direct empirical testing is greatly needed. The experiments of this proposal are designed to probe the mechanistic overlap of AUD and aging on white matter tracks by drilling down specifically on mechanisms involving myelinating cells of the central nervous system (oligodendrocytes, OLs). We use transgenic technology and cell fate mapping to track the birth and development of oligodendroglial populations involved in myelinating frontotemporal axons to learn about the cellular processes that lead to impaired remyelination capacity after alcohol exposure in older mice. We posit that in aged animals, alcohol induces delays in OL differentiation that prevents proper myelin ensheathment of intracortical axons and advances cognitive decline. Our experimental design tackles these research questions with precision, scaling from molecular—to phenotypic—to behavior. Manipulating these cellular processes allows for testing the direct link between myelin formation and cognitive functioning. Our comprehensive assessment of cognitive abilities as a function of age and sex also fills a critical gap by dissecting differential sensitivities that are clinically important for consideration. These essential first steps provide a solid foundation for a larger project on aging and alcohol interactions and whether reversal is possible with therapeutic targeting of cellular development in humans, opening new avenues for discovery of treatment strategies for alcohol and age- related cognitive dysfunction and dementia.